Background

Tumor cells continue to evolve the metastatic potential in response to signals provided by the external microenvironment during metastasis. Platelets closely interact with tumor cells during hematogenous metastasis and facilitate tumor development. However, the molecular mechanisms underlying this process are not fully understood.

Methods

RNA-sequencing was performed to screen differentially expressed genes mediated by platelets. The effects of platelet and CD39 on tumor metastasis were determined by experimental metastasis models with WT, NCG and CD39^−/− mice.

Results

RNA-sequencing results showed that platelets significantly up-regulated CD39 expression in tumor cells. CD39 is a novel immune checkpoint molecule and a key driver of immunosuppression. Our data provided evidence that the expression of CD39 was enhanced by platelets in a platelet-tumor cell contact dependent manner. Although the role of CD39 expressed by immune cells is well established, the effect of CD39 expressed by tumor cells on tumor cell behavior, anti-tumor immunity and tumor metastasis is unclear. We found that CD39 promoted tumor cell invasion, but had no effect on proliferation and migration. Notably, we showed that the ability of platelets to prime tumor cells for metastasis depends on CD39 in the experimental tumor metastasis model. CD39 silencing resulted in fewer experimental metastasis formation, and this anti-metastasis effect was significantly reduced in platelet-depleted mice. Furthermore, overexpression of CD39 in tumor cells promoted metastasis. In order to eliminate the effect of CD39 expressed in cells other than tumor cells, we detected tumor metastasis in CD39^−/− mice and obtained similar results. Moreover, overexpression of CD39 in tumor cells inhibited antitumor immunity. Finally, the data from human samples also supported our findings.

Conclusions

Our study shows that direct contact with platelets induces CD39 expression in tumor cells, leading to immune suppression and promotion of metastasis.

中文翻译：

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血小板诱导肿瘤细胞表达CD39，促进肿瘤转移

背景

肿瘤细胞在转移过程中响应外部微环境提供的信号，继续进化出转移潜能。血小板在血行转移过程中与肿瘤细胞密切相互作用，促进肿瘤的发展。然而，这一过程背后的分子机制尚未完全了解。

方法

进行RNA测序以筛选血小板介导的差异表达基因。^{血小板和CD39对肿瘤转移的影响通过WT、NCG和CD39 −/−}小鼠的实验转移模型来确定。

结果

RNA测序结果显示血小板显着上调肿瘤细胞中CD39的表达。CD39 是一种新型免疫检查点分子，也是免疫抑制的关键驱动因素。我们的数据提供证据表明血小板以血小板-肿瘤细胞接触依赖性方式增强CD39的表达。尽管免疫细胞表达的CD39的作用已被充分确定，但肿瘤细胞表达的CD39对肿瘤细胞行为、抗肿瘤免疫和肿瘤转移的影响尚不清楚。我们发现CD39促进肿瘤细胞侵袭，但对增殖和迁移没有影响。值得注意的是，我们表明，在实验性肿瘤转移模型中，血小板启动肿瘤细胞转移的能力取决于 CD39。CD39沉默导致实验性转移形成减少，并且这种抗转移作用在血小板耗尽的小鼠中显着降低。此外，肿瘤细胞中CD39的过度表达促进了转移。为了消除肿瘤细胞以外的细胞中表达的CD39的影响，我们在CD39 ^-/-小鼠中检测了肿瘤转移，并获得了类似的结果。此外，肿瘤细胞中CD39的过度表达会抑制抗肿瘤免疫。最后，人类样本的数据也支持了我们的发现。

结论

我们的研究表明，与血小板的直接接触会诱导肿瘤细胞中 CD39 的表达，从而导致免疫抑制和促进转移。